Application of immunohistochemistry in diagnosis and management of malignant mesothelioma

Our plain-English summary of Application of immunohistochemistry in diagnosis and management of malignant mesothelioma, by D.B. Chapel, J.J. Schulte, A.N. Husain, et al (Translational Lung Cancer Research, 2020).

The study

• Authors: D.B. Chapel, J.J. Schulte, A.N. Husain, T. Krausz
• Journal: Translational Lung Cancer Research
• Published: 2020;9(Suppl 1):S3-S27
• Type of article: Review
• Cited by: 129 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Immunohistochemistry plays an indispensable role in accurate diagnosis of malignant mesothelioma, particularly in morphologically challenging cases and in biopsy and cytology specimens, where tumor architecture is difficult or impossible to evaluate. Application of a targeted panel of mesothelial- and epithelial-specific markers permits correct identification of tumor lineage in the vast majority of cases. An immunopanel including two mesothelial markers (calretinin, CK5/6, WT-1, or D2-40) and two epithelial markers (MOC-31 and claudin-4) offers good sensitivity and specificity, with adjustments as appropriate for the differential diagnosis. Once mesothelial lineage is established, malignancy-specific studies can help verify a diagnosis of malignant mesothelioma. BAP1 loss, CDKN2A homozygous deletion, and MTAP loss are highly specific markers of malignancy in a mesothelial lesion, and they attain acceptable diagnostic sensitivity when applied as a diagnostic panel. Novel markers of malignancy, such as 5-hmC loss and increased EZH2 expression, are promising, but have not yet achieved widespread clinical adoption. Some diagnostic markers also have prognostic significance, and PD-L1 immunohistochemistry may predict tumor response to immunotherapy. Application and interpretation of these immnuomarkers should always be guided by clinical history, radiographic findings, and above all histomorphology.

2020 Translational Lung Cancer Research. All rights reserved.

In plain English

This was a review article on how laboratory staining tests (immunohistochemistry) are used to diagnose malignant mesothelioma. It drew on published studies and on the authors' own diagnostic practice. It did not study asbestos exposure. The authors described routinely using a panel of two to three mesothelial markers and two epithelial markers, typically calretinin, WT-1 and/or D2-40, MOC-31 and claudin-4, to tell mesothelioma apart from carcinoma. In the studies reviewed, loss of BAP1 staining was virtually 100% specific for malignancy in mesothelial growths, but it was found in only about 50–65% of pleural mesotheliomas. CDKN2A homozygous deletion was similarly specific. Combining BAP1 and CDKN2A testing gave reported sensitivities mostly of 85–93%. In unpublished data from the authors' laboratory, 52 of 89 (58%) peritoneal mesotheliomas showed loss of the marker 5-hmC in more than half of tumor nuclei. The authors concluded that immunohistochemistry plays an ever-larger role in diagnosis, while careful examination of the tissue's appearance remains the cornerstone. They noted that several newer markers still await validation in larger studies.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published studies on immunohistochemical (staining) markers for diagnosing malignant mesothelioma, with the authors' own practice and some unpublished laboratory data
• Who was studied: Published studies of benign and malignant mesothelial lesions of the pleura, peritoneum, pericardium and tunica vaginalis, and of the carcinomas they must be distinguished from; plus unpublished series from the authors' laboratory (33 and 89 peritoneal mesotheliomas)
• Exposure: Not applicable: the review concerns diagnostic staining tests. Asbestos or other exposures were not studied.
• Main results:
  • The authors' routine lineage panel uses two to three mesothelial and two epithelial markers, typically calretinin, WT-1 and/or D2-40, MOC-31 and claudin-4
  • In the reviewed literature, claudin-4 was up to 92–100% sensitive and 94–100% specific for epithelial (carcinoma) lineage versus mesothelial lesions
  • In the reviewed literature, BAP1 loss occurred in about 50–65% of all pleural mesotheliomas: 61–77% of epithelioid, 33–49% of biphasic and 0–22% of sarcomatoid
  • In the reviewed literature, CDKN2A homozygous deletion was virtually 100% specific for malignancy in mesothelial proliferations, but only 48–88% sensitive for pleural mesothelioma (mostly 50–65%)
  • In the reviewed literature, MTAP loss was 65–88% sensitive and 96–100% specific for CDKN2A homozygous deletion, and 43–65% sensitive and up to 100% specific for mesothelioma
  • In the reviewed literature, a combined BAP1 plus CDKN2A FISH panel had sensitivity of 58–93%, mostly 85–93%
  • In an earlier published study by the authors' group (49 mesotheliomas, 23 reactive proliferations), 5-hmC loss in more than 50% of tumor nuclei was 100% specific and 92% sensitive for malignancy
  • Unpublished data from the authors' laboratory: 52 of 89 (58%) malignant peritoneal mesotheliomas showed 5-hmC loss in more than 50% of tumor nuclei
  • Unpublished data from the authors' laboratory: 1 of 33 peritoneal mesotheliomas showed MTAP loss
  • In the reviewed literature, mesothelioma with germline BAP1 mutation had 5-year overall survival of 47%, compared with 7% for non-germline-mutated mesothelioma
• The authors' conclusion: The authors concluded that immunohistochemistry plays an ever-larger role in diagnosing mesothelial lesions, with BAP1 and more recently MTAP entering routine use and newer markers under study. They also concluded that careful examination of tissue appearance (morphology) remains the cornerstone of diagnosis.
• Limitations the authors state:
  • The literature on MTAP staining covers only pleural lesions
  • 5-hmC staining has not yet been studied in small biopsies or cytology cell blocks
  • The prognostic data on EZH2 come from only two studies with 80 patients in total
  • Prognostic studies of BAP1 loss generally did not separate germline from sporadic loss
  • BAP1 loss also occurs in other tumors, so on its own it does not establish mesothelioma in all circumstances

Topics

Medical terms in this study, explained in our Lexicon: Immunohistochemistry, Mesothelioma, Biopsy, Cytology, Calretinin, Wilms Tumor 1 (WT-1), Podoplanin (D2-40), MOC-31.

Related studies

• MTAP immunohistochemistry is an accurate and reproducible surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant pleural mesothelioma — D.B. Chapel, J.J. Schulte, et al. (2020)
• Application of immunohistochemistry in the diagnosis of epithelioid mesothelioma: a review and update — N.G. Ordóñez (2013)
• Diagnostic application of BAP1 immunohistochemistry to differentiate pleural mesothelioma from metastatic pleural tumours — M. Yoshimura, Y. Kinoshita, et al. (2017)
• Immunohistochemistry: applications to the evaluation of lung and pleural neoplasms: part 2 — H. Mani, D.S. Zander (2012)
• Clinical and molecular validation of BAP1, MTAP, P53, and Merlin immunohistochemistry in diagnosis of pleural mesothelioma — D.B. Chapel, J.L. Hornick, et al. (2022)
• A review of mechanochemistry applications in waste management — X. Guo, D. Xiang, et al. (2010)

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